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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oncostatin M (OM) is a cytokine that shares a structural and functional relationship with interleukin 6, leukemia-inhibitory factor, and granulocyte colony-stimulating factor. In this report, we tested for correlations between immediate-early gene expression and some of the cellular responses elicited by OM. We determined that OM stimulated a rapid and transient elevation of EGR-1, c-jun, and c-myc mRNA in human fibroblasts prior to their proliferation. OM also stimulated a transient induction of these genes in M1 leukemic cells that differentiated into nonreplicating, macrophage-like cells. The expression of c-myc, however, decreased significantly as the cells stopped dividing. Interestingly, OM had no detectable effect on the expression of EGR-1, c-jun, and c-myc during the cell cycle arrest of human A375 melanoma cells. Our results indicate that an early nuclear event associated with OM action is the regulation of immediate-early gene expression. We suggest that the transcription factors encoded by the EGR-1, c-jun, and c-myc genes are utilized in both cell proliferation and differentiation but are not part of the mechanism by which OM inhibits A375 cell growth.
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PMID:Regulation of EGR-1, c-jun, and c-myc gene expression by oncostatin M. 163 13

Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates both the proliferation and functional properties of normal and leukemic myeloid cells via cell surface receptors. The postreceptor mechanisms for these two actions, and the extent to which they represent overlapping biochemical pathways, have not been fully clarified. We have examined the actions of GM-CSF on the expression of c-myc, an early response oncogene associated with the proliferative stimulus of growth factors. GM-CSF reduced the population doubling time of HL-60 leukemia cells from 32 hours to 25 hours, and, at concentrations that were correlated with mitogenicity, induced a rapid twofold increase in the level of c-myc mRNA. Nuclear runoff studies indicated that GM-CSF approximately doubled the transcription rate of c-myc by reversing the transcription attenuation that occurs at the exon 1-intron 1 junction. GM-CSF had no effect on the half-life of c-myc messenger RNA. The biochemical basis for the modulation of c-myc expression by GM-CSF was explored. GM-CSF treatment caused intracellular alkalinization of the cells as measured using the fluorescent probe 2', 7-bis (2-carboxyethyl)-5(and-6) carboxyfluorescein (BCECF). The sodium channel blocker amiloride prevented the GM-CSF-induced change in pH, but did not affect the stimulation of c-myc transcription by GM-CSF. Agents that increase cellular cyclic adenosine monophosphate (cAMP) levels (prostaglandin E2 and cholera toxin) blocked the actions of GM-CSF on c-myc; however, these agents also reduced the basal level of c-myc expression. GM-CSF caused a rapid (5 minutes) and transient decline in cellular cyclic guanosine monophosphate (cGMP) levels, and a slower (30 minutes) and transient decrease in cellular cAMP levels. These observations are consistent with the hypothesis that the declines in cAMP and cGMP are associated with a stimulation of HL-60 proliferation, while previously reported manipulations that elevate cyclic nucleotides are related to an inhibition of HL-60 proliferation and the potentiation of differentiation.
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PMID:Regulation of c-myc expression by granulocyte-macrophage colony-stimulating factor in human leukemia cells. 164 47

Tumor necrosis factor (TNF) is a regulatory cytokine that has pleiotropic effects on hematopoietic cell growth and differentiation. The present studies have examined the effects of TNF on the differentiation of phorbol-ester resistant human KG-la leukemia cells. Treatment with 100 U/mL of TNF or 33 nM 12-O-tetradecanoylphorbol-13-acetate (TPA) had no detectable effect on the growth of KG-1a cells. In contrast, TNF, but not TPA, induced cellular aggregation and expression of the ICAM-1 adhesion molecule in KG-1a cells. Furthermore, KG-1a cells responded to TNF, but not to TPA, with a partial down-regulation of c-myc mRNA levels and induction of M-CSF gene transcription. Previous work suggested that TNF induces M-CSF gene expression through activation of phospholipase A2 and eicosanoid production. The present studies also demonstrate that TNF stimulated phospholipase A2 activity. In contrast, there was no detectable increase in phospholipase A2 activity following TPA treatment. These results indicate that: 1) certain characteristics of the differentiated monocytic phenotype were induced by TNF in the phorbol ester-resistant KG-1a line, and 2) treatment with TNF and not TPA was associated with activation of phospholipase A2 during induction of monocytic differentiation in these cells.
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PMID:Induction of monocytic differentiation by tumor necrosis factor in phorbol ester-resistant KG-1a cells. 169 25

A rapid decrease in expression of the oncogene c-myc has been associated with the induction of differentiation of HL-60 human leukemia cells. In this manner, the treatment of a hypoxanthine phosphoribosyltransferase (HPRT)-deficient HL-60 variant (HL-60/var) with 6-thioguanine (TG) was accompanied by lower c-myc mRNA levels. This occurred in the absence of 6-thioguanosine 5'-monophosphate (TGMP) synthesis and without alterations in cellular nucleotide pool sizes. Paradoxically, inhibition of c-myc expression in the wild type HL-60 (HL-60/wt) cell, which is only weakly induced to differentiate by TG, was 5-fold more sensitive to the thiopurine (IC50 = 35 microM). Furthermore, inosine, which blocks the formation of TGMP and enhances the extent of differentiation of HL-60/wt cells, decreased the sensitivity of c-myc expression in the HL-60/wt to TG. These actions of TG and inosine on c-myc were also observed in the human colon carcinoma cell line COLO 320, further dissociating some of the effects of TG on c-myc expression from granylocytic differentiation. The hematopoietic granulocyte-macrophage colony stimulating factor (GM-CSF) elevated c-myc expression and antagonized the actions of TG on c-myc in the HL-60 cells. GM-CSF more readily antagonized the inhibitory action of TG in the HL-60/var cell line when compared to the HL-60/wt cells, restoring c-myc levels to that of the untreated controls. Hence, TG inhibited c-myc expression by two distinct mechanisms in cells which express high levels of the oncogene: a TGMP-dependent, differentiation-independent process with an IC50 of 35 microM, and a TGMP-independent action with an IC50 of 175 microM that was associated with induction of differentiation and was reversed more readily by GM-CSF.
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PMID:Inhibition of c-myc expression in human promyelocytic leukemia and colon adenocarcinoma cells by 6-thioguanine. 170 32

Seven tumors independently derived from a v-Ha-ras-expressing pre-B cell line were examined to determine the oncogene activations cooperating with v-Ha-ras in in vivo tumor progression. The pre-B cell line was generated by infection with Moloney murine leukemia virus (MoMuLV) and a MoMuLV-derived recombinant expressing v-Ha-ras. Two of seven tumors possessed a MoMuLV integration immediately upstream and in reverse transcriptional orientation to c-myc. This correlated with a 3-fold increased level of c-myc mRNA. Two other tumors displayed elevated c-myc mRNA levels, although the mechanism of enhanced expression was unclear. Thus the tumor progression of a v-Ha-ras-expressing murine pre-B cell line selects for the activation of c-myc.
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PMID:Tumorigenesis of a v-Ha-ras-expressing pre-B cell line selects for c-myc activation. 171 20

Murine myelomonocytic leukemia M1 cells have been used to examine the effects of type-beta 1 transforming growth factor (TGF-beta 1) on cellular proliferation and differentiation in monocyte-macrophage lineage. TGF-beta 1 inhibited immature M1 cell growth due to a general slowdown of the cell cycle, without arrest at any specific point. Ten nanograms per milliliter TGF-beta 1 completely suppressed phagocytic activity and adhesion to the dish surface and partially inhibited the expression of Fc receptors and vimentin during the differentiation of M1 cells induced by IL-6. IL-6-induced declines in the expression of c-myc mRNA and in the accumulation of G0/G1 cells were also partially blocked by TGF-beta 1. When treated concurrently with IL-6 and TGF-beta 1, approximately 50% of M1 cells were morphologically converted to promonocyte or monocyte-like cells, which did not exhibit the characteristics of mature macrophages. Although pretreatment with TGF-beta 1 also inhibited the IL-6-induced phagocytic activity, this inhibition was reversible. Once TGF-beta 1 was removed from the culture medium after 72 h of incubation with IL-6, the kinetics of differentiation induced by IL-6 were faster in pretreated cells than in nonpretreated cells. TGF-beta 1 appears to inhibit the IL-6 induced conversion of M1 cells at the intermediate stage of monocytic differentiation.
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PMID:Effects of type-beta 1 transforming growth factor on the proliferation and differentiation of mouse myelomonocytic leukemia cells (M1). 187 63

Among 18 thymic leukemia cell lines which have been established from spontaneous thymic lymphomas in AKR mice as well as in bone marrow chimeras which were constructed by transplanting allogeneic bone marrow cells into irradiated AKR mice, three proviral integration sites were identified; near c-myc, N-myc and pim-1 loci. No integration site specific for chimeric leukemia cell lines was found. In three thymic leukemia cell lines which contained rearranged N-myc genes, insertions of long terminal repeats (LTRs) of murine leukemia viruses were detected at 18 or 20 bp downstream of the translational termination codon. These results demonstrate that the 3' region of the N-myc gene is one of the integration targets for murine leukemia viruses in spontaneous thymic lymphomas. In these three cell lines, N-myc mRNA was stably transcribed and transcription of c-myc mRNA was down-regulated. The integrated murine leukemia viruses in AKR thymic leukemia were most likely AKV, though the DNA sequence of the LTR inserted in the genome of a leukemic cell line from [(BALB/c x B6)F1----AKR], CAK20, was different from LTRs of murine leukemia viruses so far reported.
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PMID:Provirus integration at the 3' region of N-myc in cell lines established from thymic lymphomas spontaneously formed in AKR mice and a [(BALB/c x B6)F1----AKR] bone marrow chimera. 190 Aug 22

The myc proto-oncogenes encode nuclear phosphoproteins, which are believed to participate in the control of cell proliferation and differentiation. Deregulated expression of c-myc has been implicated in several human hematopoietic malignancies. We have studied the expression and mRNA processing of human L-myc, N-myc, and c-myc genes in a panel of human leukemias, leukemia cell lines, and normal hematopoietic cells. L-myc mRNA was expressed in three acute myeloid leukemias (AML) studied and in several myeloid leukemia cell lines. Only low expression levels were observed in adult bone marrow and in fetal spleen and thymus. The K562 and Dami leukemia cell lines showed a unique pattern of L-myc mRNA processing, with approximately 40% of L-myc mRNA lacking exon III and intron I. N-myc was expressed in five of six AML cases studied, in one of nine acute lymphocytic leukemia (ALL) cases, and in several leukemia cell lines, while c-myc mRNA was detected in all leukemias and leukemia cell lines studied. Coexpression of all three myc genes was observed in Dami and MOLT-4 cell lines and in two AMLs, and either L-myc or N-myc was coexpressed with c-myc in several other cases. These results show that in addition to c-myc, the L-myc and N-myc genes are expressed in some human leukemias and leukemia cell lines, and suggest a lack of mutually exclusive cross-regulation of the myc genes in human leukemia cells.
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PMID:Expression of L-myc and N-myc proto-oncogenes in human leukemias and leukemia cell lines. 195 86

Alteration and abnormal expression of the c-myc oncogene were investigated in human multiple myeloma. Human myeloma cells were highly purified (more than 95%) from bone marrow aspirates in 14 cases of advanced multiple myelomas and one case of plasma cell leukaemia. Southern blotting revealed that a rearranged configuration of c-myc gene was found in only one case of them, but this was a novel truncation of the gene in its coding exon II; a rearranged 3.4 kb band was detected by digestion with Xba I using c-myc exon II probe, but no rearranged band was found using exon III probe. In this case, the truncated c-myc allele was not transcribed; normal sized (2.4 kb) c-myc mRNA was markedly expressed, but no aberrant mRNA was detected. On the other hand, by Northern blotting, the nine cases, including the case with the rearranged c-myc gene, showed increased expression of normal sized (2.4 kb) c-myc mRNA. Elevated c-myc mRNA expressions were well related to the in vitro proliferation (3H-TdR uptake), but not to IL-6 response. Interestingly, extremely high expressions of c-myc mRNA were detected in two cases of aggressive myelomas, including the case with the rearranged c-myc gene, and in one of plasma cell leukaemia. These two cases of aggressive myelomas were the ones who showed the markedly high 3H-TdR uptakes, and had the common clinical features with the formation of an extramedullary mass and very short survival. These results suggest that the activation of c-myc gene could induce high proliferative activities and the subsequent aggressive transformation of myeloma cells.
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PMID:Increased expression of the c-myc gene may be related to the aggressive transformation of human myeloma cells. 202 78

We have studied tumor necrosis factor alpha (TNF-alpha) for its capacity to induce differentiation and to modulate c-myc and c-fms protooncogene mRNA expression in fresh blasts from 10 patients with acute myeloblastic leukemia (AML). Bone marrow blast cells were grown in suspension cultures in the presence of 500 U/ml (62 ng/ml) of TNF-alpha for 7 days. Induction of differentiation was assessed by means of morphology, cytochemistry, immunophenotyping (CD11b, CD13, CD14, CD33), and nitroblue tetrazolium reduction. In all cases, exposure of leukemic blasts to TNF-alpha resulted in phenotypic changes consistent with induction of differentiation, although a marked variability in degree and type of response was observed. The majority of cases developed monocytic morphology and showed significant increases (chi 2 test, p less than 0.05) in phagocytic activity and/or expression of ANAE and myelomonocytic differentiation antigens (CD11b, CD14). TNF-alpha reduced c-myc mRNA level over a period of 24 hr in four of six cases studied: the two cases with no down-regulation were the least responsive in terms of myelomonocytic differentiation. These results confirm those obtained with leukemic cell lines, suggesting that TNF-alpha can induce differentiation of fresh AML blasts, mainly toward the monocytic lineage, and that induction of differentiation seems to be closely linked to down-regulation of c-myc mRNA expression over the first 24 hr rather than to attenuation of cellular proliferation per se.
Leukemia 1990 Jun
PMID:Tumor necrosis factor alpha down-regulates c-myc mRNA expression and induces in vitro monocytic differentiation in fresh blast cells from patients with acute myeloblastic leukemia. 235 42


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